Multiple sclerosis (MS) and inflammatory bowel disease (IBD) are thought to be immune mediated diseases where Th1 responses are linked to the disease process. During the course of an immune response, the T cell requires 2 signals for full activation. The first signal is provided by engagement of the TCR with the antigenic peptide plus MHC molecule on antigen-presenting cells (APCs), and the second "co-stimulatory" signal is provided by binding of specific receptors on T cells with their ligand(s) on APCs. The best characterized co-stimulatory pathway is that provided by CD28 on T cells binding to B7-1 and B7-2 on professional APCs. Another co-stimulatory signal is provided by interaction on CD40 on the surface of APCs with CD40L on the surface of T cells. There is data in several autoimmune animal models as well as in vitro data suggests that blocking the CD40-CD40L interaction would suppress disease Patients with progressive MS have increased production of IL-12, which is mediated through CD40-CD40L interactions. In previous studies we have linked several immune abnormalities to MS disease activities as measured clinically and by MRL. In this proposal we will investigate 1) The effect of anti-CD40L treatment on the state of activation in peripheral blood mononuclear cells. Our hypothesis is that anti-CD40L treatment will down-regulate the expression of activation markers on peripheral blood lymphocytes and decrease the serum level of circulating molecules associated with activation. 2) The effect of anti-CD40L treatment on immune function. Our hypothesis is that treatment with anti-CD40L will decrease IL-12 production by monocytes, and IFN-gamma production by T-cells as well as autoantibody production by B cells. 3) How does treatment with anti-CD40L affect auto-reactive cell requirement for co- stimulatory signals in MS patients. Our hypothesis is that anti-CD40L treatment may cause a change in the co-stimulatory requirements of MBP specific cells. 4) How does treatment with anti-CD40L alter the cytokine profile in intestinal biopsies of patients with IBD. Experimental animal model have shown a predominance of Th1 cells in inflamed bowel and that treatment with anti-CD40L decreased IFN-gamma secretion and increased IL-4 secretion. Our hypothesis is that patients with IBD will have a decrease in Th1 cytokines and an increase in Th2 cytokines after anti-CD40L treatment in intestinal biopsies.